Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone

BACKGROUND: This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC). METHODS: Patients with HRPC that progressed during or within 60 days of cessation of taxane chemotherapy were randomly selected with equal probability to ixabepilone 35 mg/m(2) intravenously every 3 weeks, or mitoxantrone 14 mg/m(2) intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment continued until progression or toxicity; crossover was allowed. RESULTS: Forty-one patients were accrued to each arm of the study. The median number of cycles administered for each arm was 3. Median survival from protocol entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific antigen (PSA) declines of >or=50% were observed in 17% of ixabepilone (95% CI, 7-32) and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease. Median duration of second-line ixabepilone and MP treatment was 2.2 months and 2.3 months, respectively. For third-line crossover treatment, PSA declines of >or=50% were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior taxane response was associated with an increased likelihood of second-line ixabepilone or MP response. Low baseline lactate dehydrogenase and absence of visceral metastases independently predicted improved survival. The most common grade 3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabepilone patients and 63% of MP patients). CONCLUSIONS: Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months.     

First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer: does sequence matter?

BACKGROUND: Docetaxel and mitoxantrone are considered first-line chemotherapeutic options in patients with hormone-refractory prostate cancer (HRPC), but their clinical effectiveness in a second-line setting is unknown. Therefore, the authors conducted a population-based retrospective study to establish activity and tolerability of second-line docetaxel or mitoxantrone in HRPC. METHODS: The study included 68 patients who had failed androgen ablation therapy and who received docetaxel and mitoxantrone in either sequence. Clinical efficacy in terms of median overall survival (OS), progression-free survival (PFS), posttreatment prostate-specific antigen (PSA) decline of > or = 50% and treatment-related toxicity were evaluated. RESULTS: Of 68 patients, 35 received docetaxel followed by mitoxantrone, and 33 received mitoxantrone followed by docetaxel. Both groups were comparable for recognized pretreatment prognostic factors. Patients who received docetaxel first-line had a trend toward longer median OS compared with patients treated with second-line docetaxel after mitoxantrone failure (22 mos, 95% confidence interval [CI], 17.2-26.8 mos vs. 15 mos, 95% CI, 10.4-19.6 mos). Median number of second-line chemotherapy cycles was 3 and median PFS survival was 2-3 months in both groups. Second-line docetaxel produced a higher PSA response compared with mitoxantrone (38% vs. 12%, P = 0.012), but this did not translate to a survival benefit. Both second-line docetaxel and mitoxantrone were associated with a high frequency of treatment-related adverse events that resulted in dose reduction, delay, or discontinuation (64% and 46% of patients, respectively). CONCLUSIONS: Study results favored docetaxel given up-front for patients with HRPC considered suitable for further chemotherapy. Second-line docetaxel or mitoxantrone had limited efficacy and tolerability. Patients who are candidates for second-line chemotherapy, should be enrolled into clinical trials.     

Ixabepilone,mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

BACKGROUND:

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second‐line chemotherapy in patients with docetaxel‐refractory castration‐resistant prostate cancer. Clinical noncross‐ resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose‐limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.

METHODS:

Patients with metastatic progressive castration‐resistant prostate cancer during or after 3 or more cycles of taxane‐based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m² and mitoxantrone 12 mg/m² administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.

RESULTS:

Results are reported for the 56 evaluable patients. Twenty‐five (45%; 95% confidence interval [CI], 31%‐59%) experienced confirmed ≥50% prostate‐specific antigen (PSA) declines, 33 (59%; 95% CI, 45%‐72%) experienced confirmed ≥30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%‐39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5‐5.6), and median progression‐free survival was also 4.4 months (95% CI, 3.0‐6.0). Median overall survival was 12.5 months (95% CI, 10.2‐15.9). Thirty‐two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment‐related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.

CONCLUSIONS:

These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration‐resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;. © 2010 American Cancer Society.     

Phase II study of sequential chemotherapy with docetaxel-estramustine followed by mitoxantrone-prednisone in patients with advanced hormone-refractory prostate cancer

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m(-2) intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m(-2) i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3-4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63-82%) obtained a >/=50% PSA decline with 15 patients (37.5%; 95% CI 20-50%) that demonstrated a >/=90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8-8.2 months) and 19.2 months (95% CI 13.9-24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.     

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer.

PURPOSE: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. RESULTS: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. CONCLUSIONS: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.     

Is it reasonable to consider second-line chemotherapy in patients with hormone-refractory prostate cancer?

At present, no consensus exists regarding the use of second-line chemotherapy in patients with hormone-refractory prostate cancer (HRPC). A total of 23 patients with evidence of disease progression during or after first-line chemotherapy (epirubicin, etoposide, and dexamethasone) were included in this study. Two second-line treatments were administered throughout the study period (2000-2004) with 15/23 patients receiving carboplatin AUC 3 on day 1 and vinblastine 5 mg/m2 on day 1 of a 21-day cycle and 8/23 patients treated with docetaxel 50 mg/m2 on day 1 of a 21-day cycle. The latter regimen has been used since 2003. The prostate-specific antigen (PSA) level decreased by > or =50% in 3 of 23 patients, corresponding to an overall PSA response rate of 13% (95% confidence interval, 3-34%). The median time to biochemical progression was 9, 24 and 33 weeks, respectively. The median overall survival was 39 weeks (range, 15-73 weeks) with no difference between the two chemotherapy groups (p=0.08). A significant reduction of analgesic use was observed in 2 of 10 patients (20%) who required analgesics for cancer pain upon study entry. The major toxicity was grade 3 thrombocytopenia in 2 of 23 patients (9%). Both second-line treatments, a combination of carboplatin and vinblastine and a monotherapy with docetaxel, showed modest activity at subtoxic doses in patients with HRPC.     

Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer.

PURPOSE: To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. RESULTS: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. CONCLUSION: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.     

Survival prolongation after treatment failure of first-line chemotherapy in patients with advanced gastric cancer: combined analysis of the Japan Clinical Oncology Group Trials JCOG9205 and JCOG9912

Background

Two randomized phase III trials of first-line chemotherapy for advanced gastric cancer (JCOG9205 and JCOG9912) conducted by the Japan Clinical Oncology Group used 5-fluorouracil continuous infusion (5-FUci) as the control arm. New active agents (e.g., S-1, irinotecan, and taxanes) were introduced as second-line chemotherapy in the late 1990s after JCOG9205. This combined analysis evaluated whether patients in the 5-FUci arm of JCOG9912 exhibited better survival after adjusting for baseline factors and also investigated the cause of survival prolongation.

Patients and methods

The subjects were patients assigned to the 5-FUci arms who met the eligibility criteria of both JCOG9205 and JCOG9912. Overall survival (OS), time to treatment failure (TTF), and survival after treatment failure in the first-line chemotherapy (OS-TTF) were compared after adjusting baseline characteristics using the Cox proportional hazard model. Second-line chemotherapy details were also reviewed.

Results

The combined analysis included 89 and 230 patients in JCOG9205 and JCOG9912, respectively. After adjusting baseline characteristics, TTF was similar between groups (HR 0.95; 95 % CI, 0.73–1.26). However, both OS (HR, 0.74; 95 % CI, 0.56–0.99) and OS-TTF (HR, 0.76; 95 % CI, 0.57–1.01) were longer in JCOG9912. More patients in JCOG9912 received second-line chemotherapy (83 vs. 52 %) with new drugs (77 vs. 10 %) than in JCOG9205. OS-TTF was substantially prolonged in patients who received second-line chemotherapy (HR, 0.66; 95 % CI, 0.46–0.95).

Conclusion

OS and OS-TTF were longer in JCOG9912 than JCOG9205. Second-line chemotherapy with new drugs is a potential reason for the observed prolongation of survival.     

A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel

BACKGROUND: Prostate cancer is the second leading cause of cancer mortality among men in the U.S. To the authors' knowledge, there is no proven, effective, second-line therapy for docetaxel-refractory disease. Recent data suggest that platinum salts may be effective when combined with taxanes in metastatic hormone-refractory prostate cancer (HRPC). The authors conducted a phase 2 trial of docetaxel plus carboplatin chemotherapy in this disease setting. METHODS: Eligible men had metastatic HRPC that had progressed during or within 45 days after the completion of docetaxel-based chemotherapy. Patients were treated with intravenous docetaxel at a dose of 60 mg/m(2) plus carboplatin at an area under the curve of 4 once every 21 days until they had either disease progression or unacceptable toxicity. RESULTS: Thirty-four patients were enrolled. Therapy was tolerated reasonably well; Grade 3 leukopenia (graded according to the Common Toxicity Criteria grading system) was the most common adverse event (experienced by 56% of patients), but there was only 1 episode of febrile neutropenia reported. Prostate-specific antigen (PSA) declines > or =50% were noted in 18% of patients, and measurable responses were observed in 14%. The median duration of PSA response was 5.7 months. The median progression-free survival was 3 months, and the median overall survival was 12.4 months. Patients were more likely to respond to the combination if they previously had responded to docetaxel. CONCLUSIONS: In men with HRPC who developed progressive disease during or shortly after treatment with docetaxel, the addition of carboplatin resulted in modest additional activity. Taxane-refractory HRPC is an area of unmet need, and the current trial has provided evidence that platinum chemotherapy may be an important therapeutic option.     

Is there a role for platinum chemotherapy in the treatment of patients with hormone‐refractory prostate cancer?

Docetaxel chemotherapy is the current standard of care for metastatic hormone-refractory prostate cancer (HRPC). Platinum chemotherapy drugs, such as cisplatin and carboplatin, have moderate single-agent activity in HRPC. Next-generation platinum drugs, including satraplatin and oxaliplatin, may have additional activity in the management of HRPC. Furthermore, neuroendocrine differentiation may play a role in disease progression, providing a rationale for platinum-based chemotherapy in the management of HRPC. The authors reviewed the MEDLINE database for reports related to platinum-based chemotherapy in patients with advanced prostate cancer and evaluated studies that reviewed the role of neuroendocrine differentiation in the progression of HRPC. Older studies from the 1970s and 1980s suggested a lack of activity of cisplatin and carboplatin; however, those studies were flawed at least in part by their methods of response assessment. More recent Phase II studies of carboplatin suggested a moderate level of clinical and palliative activity when it was used as a single agent. However, when carboplatin was combined with a taxane and estramustine, high response rates were observed in several recent clinical trials. In addition, a randomized trial suggested that satraplatin plus prednisone improved progression-free survival compared with prednisone alone. For patients who progressed after docetaxel, no standard options existed in the literature that was reviewed. Several preliminary reports suggested that carboplatin and oxaliplatin may have activity as second-line chemotherapy. Platinum chemotherapy drugs historically have been considered inactive in HRPC, although a review of the data suggested otherwise. Carboplatin, in particular, induced very high response rates when it was combined with estramustine and a taxane, but it also appeared to have activity in patients who progressed after docetaxel. Satraplatin plus prednisone is being investigated in a large Phase III trial as second-line chemotherapy for HRPC. Targeting neuroendocrine cells may provide a new therapeutic approach to HRPC.     

Second-line systemic treatment for advanced cholangiocarcinoma

Background

Gemcitabine plus platinum (GEM-P) combination chemotherapy is standard treatment for first-line advanced cholangiocarcinoma (aCC). GEM-P first-line therapy reports a progression-free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Treatment in the second-line setting is less clear. Five-year survival for aCC remains dismal at 5-10%. The purpose of this study was to describe the outcomes with second-line systemic treatment at our institution.

Methods

This study was a single institution retrospective chart review of aCC patients who initiated second-line systemic treatment during 1/1/2009 to 12/31/2012. The primary objective was to evaluate PFS with second-line systemic treatment. Secondary objectives were OS and disease control rate. Second-line systemic regimens were classified into four treatment groups: GEM-P, gemcitabine + fluoropyrimidine (GEM-FU), other FU combination (FU-combo), and others.

Results

Fifty-six patients were included and the majority had intrahepatic aCC. A total of 80% received first-line gemcitabine-based therapy. Second-line therapy consisted of GEM-P (19.6%), GEM-FU (28.6%), FU-combo (37.5%), and others (14.3%). Median PFS was 2.7-month (95% CI, 2.3-3.8 months) with a median OS of 13.8 months (95% CI, 12-19.3 months) and a disease control rate of 50%. No significant difference in survival was identified between the four treatment groups.

Conclusions

This study revealed a 2.7-month PFS, 50% disease control rate, and potential survival benefit with second-line treatment. Options for second-line systemic therapy include GEM-FU, FU-combo, GEM-P if not given in the first-line setting. Targeted therapy with erlotinib or bevacizumab could be considered in addition to chemotherapy.     

Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group trial S0111.

PURPOSE: The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS: Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response. RESULTS: Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months). CONCLUSION: Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.     

Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?

No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20-40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16-2.77; P=0.008), haemoglobin 50 ng ml(-1) (HR, 1.86; 95% CI, 1.21-2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16-2.53; P=0.006), and time-to-progression under first-line chemotherapy 相似文献   

Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin

Purpose

A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline.

Methods

During the 2000?C2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed.

Results

Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ???or?<6?months was demonstrated to be significantly associated with the response to second-line chemotherapy (P?=?0.0026), progression-free survival (P?=?0.0003) and overall survival (P?=?0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6?months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641?C7.388, P?=?0.0012, and 2.341, 95% CI, 1.034?C5.301, P?=?0.042, respectively).

Conclusions

Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6?months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.     

Chemotherapy for advanced prostate cancer: Results of new clinical trials and future studies

Our understanding of the role of chemotherapy for advanced prostate cancer has improved considerably in 2004 with the publication of two large randomized phase III trials and the approval by the US Food and Drug Administration of docetaxel and prednisone for metastatic hormone-refractory disease. Although treatment is still considered palliative in nature, studies of chemotherapy for metastatic hormone-refractory prostate cancer (HRPC) have demonstrated improved overall survival compared with older regimens as well as clinically significant improvements in important endpoints, such as quality of life and time to progression. In particular, docetaxel has emerged as first-line therapy on an every-3-week schedule for metastatic HRPC, replacing mitoxantrone, as recently reported in the TAX327 trial. Docetaxel and estramustine combinations have the disadvantage of significant cardiovascular and gastrointestinal toxicity, and further use of estramustine is likely unwarranted as first-line therapy. Future trials examining novel biologic agents and combination therapies should use single-agent docetaxel as the reference standard. The role of chemotherapy for advanced disease in the neoadjuvant or adjuvant setting, in biochemically (PSA) relapsed patients, and as second-line therapy for relapsed disease, remains a subject of active clinical investigation.     

Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial

Patients with metastatic triple-negative breast cancer (TNBC) typically have a poor prognosis and limited treatment options. To determine the impact of combining bevacizumab with second-line chemotherapy in patients with metastatic TNBC, we performed an exploratory subgroup analysis of the randomized phase 3 RIBBON-2 trial. RIBBON-2 enrolled patients with metastatic breast cancer that had progressed on first-line non-bevacizumab-containing chemotherapy. After selection of chemotherapy (taxane, gemcitabine, capecitabine, or vinorelbine), patients were randomized 2:1 to receive chemotherapy with either bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Of 684 patients treated in RIBBON-2, 159 (23%) had TNBC. Baseline characteristics were reasonably balanced in the two treatment groups. The majority received taxane chemotherapy. The hazard ratio (HR) for PFS was 0.494 [95% confidence interval (CI) 0.33-0.74; P = 0.0006]. Median PFS was 6.0 months with bevacizumab-chemotherapy versus 2.7 months with chemotherapy alone. Median OS was 17.9 versus 12.6 months, respectively (HR 0.624, 95% CI 0.39-1.007; P = 0.0534). ORR was 41 versus 18%, respectively (P = 0.0078). The safety profile was consistent with the overall study population and previous phase 3 trials of bevacizumab. Patients with metastatic TNBC derived significant PFS and response benefits from the combination of bevacizumab with second-line chemotherapy. Despite the small sample size and immature data, there was a trend toward improved OS.     

Characterization of prognostic factors and efficacy in a phase-II study with docetaxel and estramustine for advanced hormone refractory prostate cancer

BACKGROUND: Docetaxel based chemotherapy not only reduces pain and improves quality of life in advanced hormone refractory prostate cancer (HRPC), but it also improves survival. We investigated the combination of docetaxel and estramustine in patients with HRPC regarding efficacy and prognostic parameters. PATIENTS AND METHODS: We conducted a phase-II trial, administering docetaxel (70 mg/m(2) i.v., day 2, every 3 weeks) and estramustine (280 mg 3 times daily p.o., 1 day prior to docetaxel, on 5 consecutive days) to patients with HRPC. Patients were monitored for PSA (prostate-specific antigen) response and toxicity. RESULTS: 62 patients were treated. The median age was 67.5 years, the median PSA was 177.9 ng/ml. The median number of cycles was 6. The median time to progression (TTP) and median survival time were 14 (+/-2) and 24 (+/-5) months, respectively. A = 50% decrease in PSA levels from baseline occurred in 38 (61.3%) patients of whom 25 (40.3%) had a = 75% PSA decrease. The main grade 3-4 hematologic toxicities were neutropenia 34% and anemia 18%. CONCLUSIONS: The combination of docetaxel and estramustine exerts substantial activity in HRPC suggesting an overall survival benefit with manageable toxicity. This trial also demonstrated a survival advantage for patients with early chemotherapeutic intervention. We identified PSA relapse, baseline PSA and hemoglobin as valuable prognostic factors in this setting.     

Prostate-specific antigen doubling time before onset of chemotherapy as a predictor of survival for hormone-refractory prostate cancer patients.

BACKGROUND: We evaluated the possible use of prostate-specific antigen doubling time (PSA-DT) before chemotherapy initiation as a surrogate marker of survival in hormone-refractory prostate cancer (HRPC) patients. PATIENTS AND METHODS: Data from 250 consecutive metastatic HRPC patients treated with chemotherapy between February 2000 and November 2006 were retrospectively analysed. At least three PSA assays were required within 3 months before chemotherapy. PSA-DT was calculated as ln 2 divided by the slope of the log PSA line, and the difference between two log PSA levels was divided by the time interval. The primary endpoint was overall survival (OS). Survival rates according to PSA-DT were stratified on chemotherapy regimen. Multivariate Cox regression analysis was performed to isolate the impact of PSA-DT on OS, controlling for associate prognostic covariates. RESULTS: Patients received docetaxel- (82%) or mitoxantrone-based chemotherapy. The median PSA-DT was 45 days (range 4.7-1108 days). There were 174 deaths (70%). The median survival was 16.5 months (95% confidence interval [CI] = 12.5-20.5) and 26.4 months (95% CI = 20.3-32.4) for patients with a PSA-DT < 45 and > or =45 days, respectively. In the multivariate setting, the adjusted hazard ratio (HR) was 1.39 (95% CI = 1.03-1.89; P = 0.04), stratified by chemotherapy regimen. CONCLUSION: A short PSA-DT before onset of chemotherapy in HRPC patients was associated with an increased risk of death. This could be useful as a stratification parameter in trials with new drugs in a metastatic setting.     

Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B.

PURPOSE: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m(2), oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. RESULTS: Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease. CONCLUSION: This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone.     

Ixabepilone: clinical role in metastatic breast cancer

Ixabepilone has shown promising clinical data in metastatic breast cancer (MBC) and may be particularly valuable in patients showing progression after treatment with standard chemotherapy. This article reviews the developing clinical profile of ixabepilone in MBC. Unlike taxanes and anthracyclines, ixabepilone has low susceptibility to multiple mechanisms of tumor cell resistance and has activity against tumors resistant to taxanes and/or anthracyclines. In phase II studies, single-agent ixabepilone resulted in objective response rates ranging from 11.5% to 57% in patients who had locally advanced or metastatic breast cancer, including patients who were treated as first-line therapy or in resistant patients who had received multiple lines of previous treatment. In two large phase III studies in women who had locally advanced or MBC pretreated with or resistant to taxanes and/or anthracyclines, a combination of ixabepilone plus capecitabine was superior to capecitabine alone in terms of progression-free survival and response rates. The efficacy of ixabepilone has also been shown in subsets, including patients with poor prognosis, the first-line metastatic setting, and in triple-negative disease. Studies are underway to investigate this agent in combination with biologics. A recent three-arm study has shown the activity and tolerability of ixabepilone plus bevacizumab; however, comparative data are not yet available. The toxicity profile of ixabepilone is generally manageable and predictable. The most common adverse events associated with ixabepilone include peripheral neuropathy and neutropenia. Ixabepilone appears to offer a promising alternative chemotherapeutic agent for patients with MBC who progress on various taxanes, anthracyclines, and capecitabine.